Topical chemo-immunotherapy converts a pro-tumorigenic tumor microenvironment to a pro-inflammatory phenotype in human cutaneous squamous cell carcinoma

Abstract

Abstract We have previously demonstrated that microneedle array (MNA) delivery of anti-tumor agents improves survival in mouse models of melanoma and non-melanoma skin cancers and induces cell death in freshly excised human cutaneous squamous cell carcinomas (cSCCs). As tumors employ strong immunosuppressive and tumor-promoting mechanisms that prevent their elimination by immune surveillance mechanisms and support their proliferation, we sought to determine if application of MNAs containing anti-tumor agents could abrogate their protumorigenic phenotype and promote an anti-tumor phenotype in a human model of cSCC, the second most common human malignancy worldwide. To accomplish this, we compared Nanostring gene expression data from human cSCCs treated with MNAs containing doxorubicin (MNA-Dox) to matched, untreated cSCC controls and unmatched normal skin. As compared to matched, untreated cSCC controls, MNA-Dox-treated cSCCs demonstrated significantly decreased expression of genes associated with a pro-tumorigenic environment, including IDO, ARG2, S100A7 and VEGF-A. Further, MNA-Dox-treated cSCCs demonstrated significantly increased expression of genes associated with an anti-tumor phenotype, including CXCL14, HMGB1, P53, and Caspase-8. Comparison of MNA-Dox-treated cSCCs and unmatched, untreated normal skin suggested a reversion of a pro-tumorigenic phenotype to a normal skin phenotype, with similarly low expression of pro-tumorigenic genes seen in both groups. Together, these results suggest the potential of MNA-administered doxorubicin to effectively transform a pro-tumor microenvironment to one favoring the induction of tumor immunity in a human cSCC.